Lobular Carcinoma in Situ: Recent Clinicopathologic Studies at Memorial Hospital

Path. Res. Pract, 166, 430-455 (1980)

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York

Lobular Carcinoma in Situ: Recent Clinicopathologic Studies at Memorial Hospital* P.P.ROSEN

Summary Lobular carcinoma in situ (LCIS) is a multicentric, often bilateral form of mammary carcinoma that can only be identified and diagnosed by microscopic examination. About 75% of women whose only disease is LCIS are premenopausal. About 5010 of mastectomy specimens contain unsuspected invasive carcinoma after a biopsy revealed only LCIS. Axillary metastases occur in 1010 or less of women with LCIS when no invasive carcinoma can be detectecd. The risk of subsequent carcinoma following diagnosis of LCIS by biopsy without mastectomy was 9 times greater than in a control population. Deaths due to breast carcinoma were nearly I I times more frequent than expected. Subsequent carcinoma occurred with equal frequency in either breast. We have not been able to identify any clinical, epidemiological or pathological features that would predict which patients are most likely to develop subsequent carcinoma. Until effective methods of nonsurgical treatment or for the detection of microscopic invasive carcinoma become available, the risk of lifetime follow-up may sometimes be an acceptable alternative to the certainty of cure by mastectomy. The recommendation for follow-up should be made with a clear explanation of the risks and responsibilities involved for patient and physician. Until it can be determined whether this investigative approach will result in a substantial reduction of deaths due to breast carcinoma, it is considered prudent in most cases to recommend ipsilateral mastectomy generally with low axillary dissection and to perform a generous contralateral biopsy. The current recommendations for therapy are all far from ideal. There remains a need for well designed, prospective studies to investigate: a) factors which might identify LCIS patients with a high or low risk for subsequent carcinoma, and b) the effects of chemotherapy, antiestrogens, other medications and radiation on the long-term risk for subsequent carcinoma in patients not treated surgically.

I. Lobular Carcinoma in situ - Background Studies A. Original Description The importance of Foote and Stewart's original report can best be appreciated from a listing of the characteristics of lobular carcinoma in ':. Supported by the Brian Picolio Cancer Research Fund.

Lobular Carcinoma in Situ . 431

situ that they described. These included: a) the fact that LCIS was not detectable clinically or by gross inspection of breast tissue; b) multicentricity; c) "Pagetoid" growth in the intramammary epithelium of ducts; d) absence of Paget's disease of the nipple; e) coexistence with other types of carcinoma; and f) the potential to progress to invasive small cell carcinoma . Because of multicentricity and the potential for developing invasive carcinoma, Foote and Stewart concluded "that simple mastectomy is essential, with further procedures dependent on finding the least evidence of infiltration" .

B. Additional Descriptive Features Later studies revealed two other important characteristics of lobular carcinoma in situ; bilaterality and association with a premenopausal status. 1. Bilaterality: The reported frequency of bilaterality is dependent on how carefully it is looked for (Urban, 1967). In a recent description of his experience with contralateral breast biopsy, Urban (1969) reported finding concurrent carcinoma in the opposite breast of 45% (ro/az) of women who had LCIS in one breast. Lobular carcinoma in situ was the only contralateral lesion in 90% of the cases with simultaneous contralateral carcinoma.

2. Menstrual status: For the most part, menstrual status has been defined in terms of age. A number of authors noted that most women with LCIS were premenopausal at the time of diagnosis (Newman, 1963; Lewison and Finney, 1968; Donegan and Perez-Mesa, 1972; Andersen, 1974; Rosen et al., Surgery, 1979). The average age of the patients with LCIS has been reported to be between 44 and 46 years. This is approximately ten years earlier than the average age for infiltrating duct carcinoma and nearly IS years prior to the average onset of infiltrating lobular carcinoma.

C. Follow-up Untreated Lobular Carcinoma in situ After Foote and Stewart's paper, a series of case reports described additional instances of' progression to invasive carcinoma but it was evident that some patients might not develop invasive carcinoma even after considerable follow-up (Godwin, 1952; Barnes, 1959; Benfield et al., 1965). The first long term follow-up of untreated lobular carcinoma in situ was described in 1967 by McDivitt et al. who projected a 20 year cumulative risk of 35% for subsequent ipsilateral carcinoma and 25% for the contralateral breast. It is important to note that this report indicated for the first time that the risk of subsequent carcinoma might be equal or nearly so for both

432 . P. P. Rosen

breasts. 'Two years later Hutter and Foote (1969) reported that 30% of subsequent carcinomas had not appeared until 15 or more years after the diagnosis of LCIS. It is beyond the scope of this presentation to describe other follow-up studies published between 1968 and 1977. 'The reader is referred to a summary by Anderson (1977) and our recent critical review (Rosen and Lieberman, 1978).

D. Summary of Background Studies Lobular carcinoma in situ is a multicentric, frequently bilateral form of mammary carcinoma that can only be diagnosed by microscopic examination. 'The average age of patients with LCIS is about 47 years. 'The majority of women are premenopausal. Women with LCIS not treated by mastectomy have a substantial risk of developing invasive carcinoma later. 'The risk for either breast is approximately equal. Some carcinomas appear more than 15 years after diagnosis, but it appears that the majority of patients do not develop subsequent carcinoma.

II. Unanswered Questions and Controversies A number of specific points are still undefined or controversial. 'The remainder of this discussion will address these questions in light of our recent studies. The topics to be considered are the following: 1.

The recommendation that lobular carcinoma in situ be renamed "Lobular neoplasia";

2.

Relationships between age, menstrual status and hormone usage in patients with LCIS;

3. The frozen section diagnosis of LCIS;

4. 'The frequency of occult invasion and of axillary metastases in patients with LCIS at biopsy; 5. 'The long term follow-up of untreated intraductal carcinoma and com-

parisons with LCIS; 6. 'The lifetime risk for the development of subsequent invasive carcinoma among women with LCIS who did not undergo mastectomy; 7. 'The identification of predictive factors linked with a high or low risk for subsequent carcinoma after untreated LCIS; 8. Current recommendations for treatment; and 9. Areas for future investigation.

Lobula r Car cinoma in Situ . 433

III. James Ewing, Sir G. Lenthal Cheatle and the "Precancerous state": Implications for Lobular Carcinoma in situ and Lobular Neoplasia Haagensen et al. (1978) ha ve suggested that Ewi ng's use of the term "precancerous" to describe LCIS is justification for the alt ernative designation of "lobula r neoplasia ". Before accept ing th is app eal to historical precedent, it is appropriate to examine what Ewing seems to ha ve meant when he referred to LCIS as "precancerous" . Consideration must also be given to the view of his contemporary, Sir G. Lenthal Cheatle, a British sur geon and distinguished student of diseases of the breast. Carcinoma arising in the lobular epithelium of th e breast has been recognized for decades and w as usually included with other lesions under th e general heading of acin ar carcinoma. Earlier investigtors recognized

F ig. Y. Th is picture, pu blished by Cornil in 1908 to illust rate a stage in th e development of "ac ina r car cinoma ", is acceptable as lobular carcino ma in situ today .

434 . P. P. Rosen

non-invasive and invasive forms of the lesion designated by Foote and Stewart as lobular carcinoma in 1941. Indisputable representations of lobular carcinoma can be found in the work of Cornil published in 19°8 (Fig. 1-2) and of Salomon published in 1913 (Fig. 3-4). Both authors used the term acinar carcinoma for the disease. Terminology used to refer to the preinvasive form of lobular carcinoma in the past reflected the evolution of the concept of in situ or non-invasive carcinoma. Ewing described typical examples of lobular carcinoma in situ as "precancerous changes" and "atypical epithelial proliferation" in his book Neoplastic Diseases in 1928 and 1934 (Fig. 5). The corresponding text in which he discussed the "Prencancerous Stage of Tumor Growth", made no mention of intraepithelial carcinoma as an entity except to indicate that "precancerous changes" might be traceable from hyperplasia to a stage in which" ... other cells show more active proliferation, increase in size and in nuclear chromatin; their polarity is lost by growth of roundcells and connective tissue, and it is possible to trace such cells into types closely approaching those seen in early carcinoma". He concluded that

Fig. 2. A higher magnification from Cornil of certin features of "acinar carcinoma" Absent basement membrane (a), mononuclear infiltrate (c) and single-file orientation of infiltrating carcinoma cells (m) were noted.

Lobular Ca rcinoma in Situ . 43 5

A

Fig. 3. Th is low magnificat ion illustration from Salomon in 1913 (his Fig. 20) shows the characteristic linear growth pattern of infilt rating lobular carcinoma and the special tendency for growth within (A) as well as around lobul es (B).

Fig. 4. The intralobular portion of a lesion such as show n in Fig. 3 was show n in greater detail by Salo mon ( 1913) in th is pictur e (his Fig. 10). The simila rity of cells remain ing in the acini and the infiltrating carc inoma is evident .

436 . P. P. Rosen

Fig. 5. James Ewing .illustrated this lesion as a "precancerous change" in the third edition of his book published in 1928. Today, it would be interpreted as lobular carcinoma in situ. (Reproduced with permission - copyright W. B. Saunders, Philadelphia).

these changes "... seem to form a common preliminary to the onset of true cancer". It would appear, therefore, that Ewing probably recognized the existance of intraepithelial carcinoma. This interpretation of Ewing's use of the term "precancerous" is reinforced by the following quotation from his book that links the phrase "precancerous" with intraepithelial carcinoma and refers to the work of Sir G. Lenthal Cheatle: "Cheatle's study of the cancerous breast has furnished substantial confirmation of the importance of precancerous changes in the orzgin of many mammary carcinomas . . . . atypical prolijeratton occurs and the cells exhibit some, but not all the signs of malignancy, while still remaining within the ducts or acini. To this condition he would restrict the term "precancerous state". Finally, the cells pass beyond the limits of ducts or acini and invade the tissues. In many cases he finds the precancerous foci withm the cancel Ol/S areas. I have been able to confirm these observations in much of Cheatle's material ... as well as in my own material.

Ewing's interpretation of Cheatle's conclusions was published before the volume by Cheatle and Cutler titled Tumors of the Breast appeared in

Lobular Carcinoma in Situ . 437

Fig. 6. A black and white reproduction of color Plate II from Cheatle and Cutler (1932). Their legend described A, AI and C as terminal ducts, B as acini, D as "hyperplastic" elastica, and E-F as mammary stroma with infiltrating carcinoma. This carcinoma arose in the right breast of a 49 year old. At mastectomy, there were axillary metastases and the patient died of distant metastases in 2 112 years. The legend stated that the ducts and acini were" ... full of a malignant looking epithelial neoplasia that is still confined within normal boundaries". There was also mention of "... the connective tissue of the breast in which carcinoma cells are present. " (that) ... exactly resemble morphological appearances of the primary epithelial neoplasia inside the ducts and their acini". (Reproduced with permission - copyright J. B. Lippincott, Philadelphia).

1932. In fact, Cheatle and Cutler were even more specific in defining in situ carcinoma than Ewing suggested as evidenced by their illustrations (Fig. 6, 7) of in situ and infiltrating lobular carcinoma, and the following quotation from their text: 29 Path. Res Pract. Vol. 1,66

438 . P. P. Rosen

Fig. 7. Cheatle and Cutler (1932) illustrated invasive carcinoma ansmg in a terminal duct with this drawing (their Fig. 109). Carcinoma cells within a terminal duct (A) were shown passing through (B) a disrupted elastica (C). (Reproduced with permission copyright J. B. Lippincott, Philadelphia).

"In the earliest carcinomata of the, breast there is always present an epithelial neoplasia that is still confined within normal boundaries. The morphological characteristics of the epithelial cells within the normal boundaries are identical with those that have invaded, and there can be no doubt that they form the primary tumor from which the invading cells originated. In these instances there is no doubt that these epithelial cells inside the normal boundaries are as biologically malignant as those that have transgressed them and are trespassing in the surrounding tissues (Plate II). From this point of view they are not "precancerous" or "potentially carcinomatous", but they are actually in a state of carcinoma. For example, in some instances it is possible to detect the actual site in a duct wall from which epithelial cell invasion is occurring from an epithelial neoplasia inside the duct. At this site of exit epithelial cells can be observed half-inside and halfoutside the lesion in the duct wall. The external halves of these particular cells cannot be described as being benign or "precancerous" or "potenually carcinomatous" (Fig. 109)· These particular cells appear to be the connecting link which proves in this instance that the cells inside the normal boundaries are as malignant as those outside and that a state of carcinoma exists in the epithelial cells that are inside the normal boundaries ... The new property possessed by epithelial cells oj being able to invade grow and metastasize in outside tissues has been acquired and transmitted by their parent cells within norrnal boundaries. The final excapc of epithelial cells into surrounding tissues is a secondary matter as far as carcinoma is concerned, although; it is af primary importance from the point o] view af the individual."

Lobular Carcinoma in Situ . 439

This statement was an explicit description of intraepithelial carcinoma and the only missing element was a specific name for this state, such as in situ carcinoma. Conclusion: The development of the concept of intraepithelial or in situ carcinoma was a logical step to be taken that has had important practical and theoretical implications. A return to such terminology as "precancerous" or the introduction of the ambiguous term "neoplasia" (Haagensen et al., 1972) is, in our opinion, retrogressive. Changing the name of the disease does not alter its biological characteristics. It does not seem locigal to rename the disease when recommending an alternative form of therapy for LCIS. Certainly, as will become evident in the following discussion, there is room for further study to determine the best form of treatment for individual patients with LCIS. In pursuing this goal, we see no merit in an alternative appelation and recommend continued use of the name lobular carcinoma in situ.

IV. Lobular Carcinoma in situ Hospital Studies

Recent Memorial

In the past year there has been an opportunity to complete several additional studies that have helped to bring LeIS into sharper focus as a disease.

A. Epidemiologic Features of Lobular Carcinoma in situ Haagensen (1971) reported that LeIS "is not found in postmenopausal women" and that "... like gross cystic disease, it disappears when women enter this phase of life". He concluded that "both lesions are in this sense hormone dependent". The suggestion that LCIS does not exist in postmenopausal women was repeated the following year by Haagensen et al. (1972) who stated that "lobular carcinoma in situ is, however, a lesion which evolves in premenopausal breasts but apparently regresses and disappears after the menopause". Despite these categorical statements, other investigators have described the occurrence of LCIS in situ alone in postmenopausal women (Lewison and Finney, 1968; Donegan and Perez-Mesa, 197 2; Andersen, 1974). We have been able to confirm this in a recent study of 59 women with LCIS (Rosen et al., Surgery, 1979). Thirty-nine patients had only LCIS. Nine of this group (23010) were postmenopausal, 21010 were menopausal and 56010 were premenopausal. When LCIS coexisted with infiltrating lobular carcinoma, 71% of the patients were postmenopausal and 46% were

440 . P. P. Rosen

postmenopausal in cases found to have duct carcinoma with LeIS. A series of 190 women with duct carcinoma without LCIS concurrently treated was also analyzed. Forty percent of those with intraductal carcinoma and 61% of those with invasive duct carcinoma were postmenopausal. In so far as could be determined by individual interviews, seven of the nine postmenopausal women with LCIS had never taken any hormone medication or knowingly used estrogen containing cosmetics. Overall, hormone usage (not necessarily close to or at the time of diagnosis) was reported by 29010 of the 59 patients who had LCIS with duct carcinoma and by 35010 of the 190 women with duct carcinoma not associated with LCIS. The average age at diagnosis of LCIS in our series, 53 years, was slightly higher than described by most other reports where it was between 44 and 48 years. The oldest women, 85 years of age with LCIS, had coexisting infiltrating duct carcinoma. Finally, it is noteworthy that Haagensen et al. (I978) have themselves recently demonstrated the existance of the lobular phase in many postmenopausal patients with LCIS. Lobules were involved in 76% of postmenopausal patients. There was no significant difference in the relative proportions of ductal and lobular phases of the disease between pre and post menopausal women.

Conclusion: These data on age and menstrual status suggest that most if not all LCIS begins in premenopausal women. It is possible that endogenous hormones play an important role in the initial development of LCIS. However, detection of the lesion in women in their sixth and seventh decades of life who have no evident source or exogenous estrogens leads us to question the importance of estrogen dependence at all stages in the evolution of LCIS. Haagensen et al. (I972) were clearly wrong in their assertion that LCIS ceases to exist in postmenopausal women. Further study of the effects of hormones on LCIS must involve accurate investigation of hormone levels in these patients to determine if abnormal hormone patterns are associated with LCIS before and/or after the menopause. It is conceivable that other hormones or their metabolites play an important role in the development, maintenance or progression to invasion of LCIS. Since invasive carcinoma develops in some but not all patients with LCIS, hormonal studies may eventually aid in the identification of women with the greatest risk to develop invasive carcinoma. As we have suggested previously (Rosen and Lieberman, 1978; Rosen et aI., 197 8), these investigations could also lead to a rationale for the non-surgical treatment of LCIS, possibly with anti-estrogenic medications.

Lobular Carcinoma in Situ . 441

B. Frozen Section Diagnosis of Lobular Carcinoma in situ We have completed two investigations of the frozen section diagnosis of lobular carcinoma during the past two years. Review of 556 consecutive breast biopsies performed during three months in 1976 (Rosen, 1978) revealed the following overall results: 26% were diagnosed as carcinoma, 69% were reported as benign and in 5010 the diagnosis was deferred. Eight (3010) of the 331 cases reported benign at frozen section proved to be carcinoma on paraffin section including six with LCIS, 1 with intraductal carcinoma and 1 with infiltrating carcinoma. A third of the deferred biopsies (10/30) ultimately were interpreted as carcinoma (6 LCIS; 4 intraductal). Thus, in the combined tally of carcinoma diagnosed after the frozen section, 57% were LCIS. The second study (Rosen et a1., Ann. Surg., 1979) resulted in more detailed information about the diagnosis of lobular carcinoma in situ. The data were obtained from a review of 1,175 women treated for carcinoma consecutively between October 1976 and August 1978. In this series there were 121 women who underwent 129 biopsies that rvealed non-invasive carcinoma at either frozen or paraffin section. Seven revealed biopsies reported as non-invasive at frozen showed invasive carcinoma on paraffin section. Thus, there were ultimately 122 biopsies in which the final diagnosis after frozen and paraffin section was non-invasive carcinoma. In nearly half of the cases (59 or 48%) carcinoma was not suspected at frozen section. Of these, 36 or 61% were lobular carcinoma in situ. Forty-nine or 40010 of the 121 patients had bilateral carcinoma. Fortyone had infiltrating carcinoma in one breast and 8 had bilateral non-invasive carcinoma. Only 4 of the contralateral non-infiltrating carcinomas were found at the time of frozen section. Twelve or 30% were deferred and in 60°/0 the frozen section was interpreted as benign. Fifty-one percent (21/41) of the non-invasive carcinomas detected in contralateral biopsies were LCIS, three of which had been recognized at frozen section. One hundred and three of the 121 patients with non-invasive carcinoma at biopsy were treated by mastectomy. Residual carcinoma was found in 59 or 57010 of breasts. Three of 53 (6010) breasts removed for intraductal carcinoma contained invasion as did 2 of 50 (4010) treated for lobular carcinoma in situ. Residual non-invasive carcinoma was detected in approximately half of all breasts. The residual disease was the same type of non-invasive carcinoma as had been found in the biopsy in at least 90010 of cases Axillary metastases were discovered in three cases, but none of these had detectable invasive carcinoma despite very extensive sampling of

442 . P. P. Rosen

breast tissue. In two instances the breast contained in situ lobular carcinoma. One of these women who presented with an enlarged axillary lymph node ultimately proved to have metastases in all three axillary levels. The third patient had intraductal carcinoma. None of the patients found to have invasive carcinoma in the biopsy or mastectomy had axillary metastases. Conclusions: Two significant conclusions can be drawn from these observations. Lobular carcinoma in situ is not likely to be diagnosed at frozen section. In two-thirds of cases, LCIS will be detected after the frozen section had been reported as benign or the diagnosis had been deferred. This circumstance, which reflects the sampling problems involved in detecting LCIS, can create a difficult clinical situation for the surgeon faced with returning to a patient with what appears to be a change in diagnosis. Unfortunately, a well intentioned desire to relieve the patient's anxiety immediately after surgery can result in failure to emphasize the preliminary nature of the benign frozen section report. In this respect, LCIS differs from other types of mammary carcinoma and it is likely that on occasion these circumstances influence the choice between surgery and clinical follow-up in the management of the disease. The second point relates to occult invasion associated with LCIS. We have previously observed that the relative proportions of invasive and non-invasive carcinoma in mastectomy specimens were related to the size of the primary tumor. Foci of invasive carcinoma were found more often associated with larger primary lesions (Rosen et aI., 1975). The low frequency (4010) of detectable invasive carcinoma is consistent with this observation and confirms results reported in two other studies that detected residual invasive carcinoma in 5010 (Shah et aI., 1973) and 6010 (Carter and Smith, 1977) of cases. Each of the studies also noted residual non-invasive carcinoma in about 2fs of cases. Clearly, therefore, multiple foci of LCIS are present in the majority of cases while occult foci of invasion and axillary metastases are very infrequent. The implications of these observations for treatment will be considered below.

C. Follow-up

0/ Untreated

Intraductal Carcinoma

Two features of LCIS have been emphasized by advocates of the term lobular neoplasia. The disease has proven to be virtually 100010 cured by mastectomy. Secondly, approximately 65% of untreated patients with this lesion do not develop invasive breast carcinoma. One curious aspect of the controversy has been the fact that so much attention has focused on non-invasive lobular lesions. Why is it that the

Lobular Carcinoma in Situ . 443

advocates of lobular neoplasia have not recommended a new name such as ductal neoplasia for intraductal carcinoma? Certainly intraductal carcinoma is also cured in virtually every case by mastectomy. And, until very recently there was no factual basis for expecting that the follow-up of untreated intraductal carcinoma would differ from that of lobular carcinoma in situ. We have recently had an opportunity to trace a small number of women with microscopic foci of intraductal carcinoma who did not undergo mastectomy. Follow-up was obtained for 15 patients an average of 22 years after biopsy (Betsill et al., 1978; Rosen and Lieberman, 1978). Invasive carcinoma was subsequently detected in 8 women (53%) after an average interval of nearly 10 years. All subsequent carcinoma was detected in the same breast as the original intraductal carcinoma. Two other patients were treated at a later date for extensive clinically detected intraductal carcinoma. Other investigators have also mentioned small groups of patients with intraductal carcinoma not treated by mastectomy. Eleven cases described by Haagensen (1971) and four reported by Kraus and Neubecker (1962) seem all to have had gross papillary tumors, rather than the minute microscopic lesions that constituted our material. There were 10 recurrences in the two series, usually within ten years. Farrow (1970) reported subsequent carcinoma in 5 of 25 cases but did not describe the type of intraductal carcinoma. Finally, Dean and Geschickter (1938) found subsequent carcinoma in 6 of 8 patients with comedocarcinoma. Combined data from all five studies indicated that 41 of 78 patients (53%) with untreated intraductal carcinoma subsequently underwent a mastectomy, usually of the same breast. There is not sufficient information in all reports to determine what proportion were treated for invasive carcinoma and it is essential to appreciate the lack of uniformity in the cases. Conclusions: The data presented suggest that subsequent invasive carcinoma occurred in about 50% of patients with untreated intraductal carcinoma and that most of the later carcinoma developed in the same breast as the original intraductal lesion. It is our conclusion that these findings support continued treatment by total mastectomy. In view of the low frequency of occult invasion or of axillary metastases, the operation probably can be limited to inclusion of a low axillary dissection (Rosen et al., Ann. Surg., 1979). Advocates of follow-up rather than mastectomy for non-invasive lesions of the lobules should note that the difference from intraductal carcinoma is a relative one. Clearly some patients with intraductal carcinoma found at biopsy do not progress to invasive carcinoma. While the tendency

444 . P. P. Rosen

to subsequent ipsilateral invasion is apparently greater for intraductal carcinoma, the true significance of this will only become apparent in a larger series followed for at least 20 years.

V. Untreated Lobular Carcinoma in situ at Memorial Hospital - 1978 We have carried out two reviews of lobular carcinoma in situ covering the 26 years between 1940-50 and 1951-65. After excluding patients with coexisting infiltrating or intraductal carcinoma in the same breast, it has thus far been possible to confirm the diagnosis in approximately 250 women with a potential follow-up ranging from 12 to 36 years. This constitutes the largest series of patients with the disease assembled in one institution with follow-up of at least 10 years. Results for patients diagnosed from 1951 to 1965, currently being analyzed, are not yet available. At present we are able to summarize the first review convering 1940-50. The data given here can be found in expanded form in our report published in 1978 (in the American Journal of Surgical Pathology). Ninety-nine women with untreated ipsilateral LCIS were studied. Follow-up information was obtained for 84 patients (Table I). The average follow-up in these cases was 24 years. Carcinoma other than the original LCIS was detected in 32 women, including 3 who underwent prior contralateral mastectomy (Table 2). A total of 39 carcinomas (7 bilateral lesions), were diagnosed. All but two patients had invasive carcinoma in at least one breast. The two exceptions were individual women with subTable

1.

Summary of follow-up status of patients with LeIS No. of Patients

Follow-up Status Alive, no prior or subsequent carcinoma

39

Treated for breast carcinoma

32

Died other causes, no prior or subsequent breast carcinoma Follow-up status unknown

13 15

Total

99

(From Rosen et al., Amer. Inc., New York)

J.

Surg. Path. 1977 - copyright by Masson Publishing USA,

Lobular Carcinoma in Situ . 445 Table

2.

Laterality of carcinoma other than original lobular carcinoma in situ No. of Patients

Subsequent IpsiIateral only

t2

Contralateral only

9

Bilateral

7

Laterality unknown Prior contralateral Total (From Rosen et al., Amer. ]. Surg. Path. 1978 - copyright by Masson Publishing USA,

Table 3. Histological types of carcinoma (From Rosen et al., Amer. ]. Surg. Path. 1978 - copyright by Masson Publishing USA, Inc., New York) Laterality Types of Carcinoma Infiltrating duct & In Situ lobular Infiltrating duct In Situ & infiltrating lobular Infiltrating duct & mtutratrnq lobular

IpSilateral

Contralateral

4 4 3 3

2 6 4 I

2

o

o

Intraductal Intraductal & In Situ lobular

1

o

In Situ lobular

I

2

Colloid (mucinous)

o

1

Tubular

o

Intraductal & infiltrating lobular

1

Lobular 23/36 (64%)

sequent unilateral intraductal and in situ lobular carcinoma, respectively. The frequency of various histological combinations is shown in Table 3. Analysis of the intervals to subsequent carcinoma revealed that 38% of all carcinomas became evident 20 or more years after the diagnosis of LeIS (32% ipsilateral and 44% contralateral). This is represented graphically in Figure 8. There was an increase in cumulative risk with increasing age and length follow-up (Fig. 8). It was also apparent that the risk of developing cancer increased as a patient entered each subsequent follow-up period. This is depicted in terms of the hazard rate in Figure 9. The hazard rate is the probability that a patient who was disease free at the beginning of an

446 . P. P. Rosen '"z 8 ~ 7 '5 6

g;

.S

5

'" 4 ~

o

~

Total

CJ lpsrtateral lZ::J Contralateral

~3

~ 2 E

:iE1 Prior

~

<5

~

~

JIJ

5 - 9 10 - 14 15 - 19 20 - 24 25 - 29 30 - 34 Intervals to development carcinoma (years)

Fig. 8. Bar graph of interval in years between initial biopsy that contained LeIS and prior or subsequent carcinoma. (From Rosen et a!', Amer. J. Surg. Path. 1978 - copyright by Masson Publishing USA, Inc. New York).

022 020 018 016 014 n; '" a: .012 "0

~ 010

"' :r

008 006 004

_ _ lpstlateral

002

----- Contralateral - - All patients

Fig. 9. Hazard rate for subsequent carcinoma related to length of follow-up. (From Rosen et a!', Amer. J. Surg. Path. 1978 - copyright by Masson Publishing USA, Inc., Inc., New York)

interval would develop clinically evident breast cancer during the interval. The hazard rate increased until at least 20 years of follow-up. Half of the patients treated for breast carcinoma other than LCIS died of the disease. When the LCIS group was compared to an age-matched population taken from the Connecticut Tumor Registry (Cancer in Connecticut 1966, 1971, 1975), the risk of cancer subsequent to LCIS was

Lobular Carcinoma in Situ . 447

Predictive Factor Family history Carcinoma Yes No Pregnancies None One or more Size of biopsy 5 cm or less 6 cm or more Cysts-i-climcal Present Not present Cysts-pathologic Present Not present Number of lobules with LCIS

Subsequent Carcinoma % Number of Total b .c Patients

12 62

5 22

42 36

19 45

7 14

37 32

31 42

9 17

29 41

19 54

8 18

42 33

55

17

17

8

31 47

1 2-5 6 or more

29 27 22

13 6 10

45 22 46

1-5 6 or more

56 22

19 10

34 46

67 11

24 5

36 45

60 18

23 6

38 33

53 25

19 10

36 40

41 25 12

14 7

34 28 67

--Lymphocytic reaction Sparse Moderate to intense Lobular distension Minimal Prominent Terminal ducts Involved Not Involved Cell type in LCIS Small Large Small & large a

Total Cases'

Vanation

III

8

numbers of cases reported are due to unavailability of

information for some predictive factors or follow-up

Percentages rounded off to nearest whole percentage C These observed differences are not statistically slgnoficant except for cell type (P < 0.05, chi-square test)

b

Table 4, Relationships between selected epidemiologic, clinical, and pathologic features of patients with LCIS and subsequent carcinoma (From Rosen et aI., Amer, ]. Surg. Path. 1978 - copyright by Masson Publishing USA, Inc., New York)

9 times greater than expected (p < o.oor) and deaths due to breast cancer after LCIS were ro.r times more frequent than expected. A number of clinical and pathological factors were analyzed in an attempt to identify those patients with LCIS who had a significantly greater likelihood of developing subsequent invasive carcinoma (Table 4). As

448 . P. P. Rosen

might be expected, subsequent carcinoma was slightly more frequent among women with a family history of breast cancer and among nulliparous patients. Both factors are known to increase the risk of carcinoma for all women, whether they have LCIS or not. However, with the exception of cell type (p < 0.05), none of these factors had significant predictive value. We are reluctant to place much reliance on this single histological criterion until more evidence is available from a larger series reviewed by one group of investigators.

VI. The Columbia-Presbyterian Medical Center Study 1978 Coincident with the publication of our study, a similar investigation (Haagensen et aI., 1978) was reported from the Columbia-Presbyterian Medical Center (CPMC). Follow-up averaging 14 years (1-42 years) was obtained from 210 women found to have LCIS between 1930 and 1972 who did not undergo mastectomy, Subsequent or prior carcinoma was detected in 36 (17.1%). When compared to State of Connecticut incidence rates for breast carcinoma, this was 7 times greater than expected. Virtually all carcinomas occurred subsequent to the diagnosis of LCIS and were equally distributed between the breasts. The cumulati ve probabilities of subsequent cancer in the ipsilateral and contralateral breast up to 15 years were 10% and 9% respectively. For the ipsilateral breast the probability increased another 12% between 16 and 25 years. The increase in risk for the contralateral breast in the same interval was 6%. The greatest risk for subsequent carcinoma was observed in women with gross cystic disease, a famil y history of carcinoma in mother or sister and LCIS (observed to expected ratio- 13.8 : I). Recommended treatment for all cases was systematic followup by palpation of the patients' breasts every four months.

VII. Comparision of Memorial Hospital and CPMC Studies Since the results of the two investigations will inevitably be compared by others, it is imperative that certain important differences between the studies be noted. A . Histological criteria for the diagnosis of LCIS There seems to be no complete agreement as to minimal criteria for the diagnosis of LCIS. While it is difficult to draw conclusions from illustra-

Lobular Carcinoma in Situ . 449

tions of these subtle lesions, some photographs provided in the CPMC paper illustrate changes that are at best borderline. For example, we would not have included in our series cases in which the only lobular lesions were those represented by Figures 6 and 7 in the CPMC report. These cases were placed in our group of atypical lobular hyperplasia where the frequency of subsequent carcinoma was substantially lower after an average followup of over 20 years. We suspect that differences in follow-up results between the two series are at least in part due to inclusion of such borderline cases at CPMC. B. Length of Follow-up of Untreated LCIS

The CPMC study was extended up to 1972 because the investigators concluded that "... a minimum of five years of follow-up is essential in the study of a slowly evolving disease like lobular neoplasia". An alternative conclusion, supported by data now available from CPMC as well as Memorial Hospital, is that the inclusion of a substantial number with follow-up of as little as 5-10 years will appreciably lower the proportion of carcinoma detected subsequent to LCIS. Thus, we observed an increasing hazard rate up to 20 years and the CPMC paper stated that "there is an increasing likelihood of the development of carcinoma in both the ipsilateral and contralateral breasts as the interval following the diagnosis of lobular neoplasia lengthens up to 25 years". Length of follow-up is an important difference between both studies and is another factor that probably contributed to the lower frequency of subsequent carcinoma in the CPMC series. It is apparent from Table 5 that only a few of the CPMC patients were followed over 20 years (170/0) when compared to the Memorial Hospital experience (630/0). Comparison at the 15 year level is not possible because of incomplete data in the CPMC senes. C. Risk Factors for Subsequent Carcinoma The CPMC report emphasized family history of breast carcinoma in either a sister or the mother and so-called gross cystic disease as factors that predisposed patients with LCIS to subsequent carcinoma. This conclusion was based on comparison with a general population statistic drawn from the State of Connecticut. The ratios of observed to expected carcinoma were stated to be as follows: LCIS without cysts or family history 5.3 : I; LCIS plus cysts without family history 6.5 : I; and LCIS, cysts plus family history 13.8 : 1.

450 . P. P. Rosen Table 5. Comparison of length of follow-up of untreated lobular carcinoma in situ Percentage of Total Casest Follow-up Interval (years)

Memorial Hospital (Total = 99)

° 1-5 6-10 I I-I 5 16-20

14 4 3 7 7

(11-20)2

2II)

12 24

(14)

(46)

II

21-25 26-3°

>3 1

CPMC (Total =

(21-3 0)2

33 (44)

19

(13) 4

CPMC - Columbia Presbyterian Medical Center Rounded to nearest whole percentage 2 CPMC data available only for IO year intervals after 10 years

I

I. Cysts: The presence of gross cysts clearly did not add much to the predisposition to cancer since nearly % of all patients had cysts and yet the risk with cysts was not appreciably increased. The association between LCIS and gross cysts probably has no specific meaning beyond the fact that cysts were themselves a frequent cause for biopsy in much of the period when these cases occurred. In our recent experience, LCIS has been associated more often with other benign, mass producing lesions since aspiration has largely replaced excisional biopsy in the treatment of cysts. Despite the decreased frequency of biopsies for cysts, we have not noted a diminution in the detection of LCIS. 2. Family History: The data provided in the CPMC study are notable for one very important omission with respect to predisposing factors and the risk of subsequent cancer. The authors reported a marked increase in risk for patients with cysts plus a positive family history but did not show what the risk was for positive family history and LCIS without cysts. Since many other investigators have established positive family history alone as a significant predisposing factor, it is likely that most of the increase in risk from 5.3: I to 13.8: I was due to the effect of family history rather than the coincidental occurrence of gross cysts.

Lobular Carcinoma in Situ . 45 I

D. Number of Patients Studied for Risk at CPMC The CPMC data regarding predisposing factors refer to 212 patients (41 + 132 + 29). In order to assess the predisposition to subsequent cancer in any given case, some follow-up would be required. Yet, follow-up was said to have been available for only 2II cases. Consequently, one patient was inappropriately included in the CMPC series for risk analysis. While this seems inconsequential, an appreciable error might have resulted had the patient been included in the group with LCIS, cysts and family history.

E. Predisposing us. Predictive Factors The CPMC data concentrated on the study of factors predisposing LCIS patients to subsequent cancer when compared to a general population. Unfortunately the incidence of the predisposing features under consideration was not reported for the control population. To accurately assess the relative contributions of LCIS and family history would require control populations in which the frequency of these features had been defined. The assessment of predictive factors reported in the Memorial Hospital study was potentially more useful clinically and did not depend on comparison with an undefined population. Groups of patients with LCIS that differed in one variable were compared with respect to the frequency of subsequent carcinoma. Thus, LCIS patients with a positive family history were compared with LCIS patients who had no family history of breast carcinoma. The goal in the study of predictive factors was to find a basis on which to distinguish between high risk and low risk patients with LCIS. As noted above, none of the features studied proved to have significant predictive value.

F. Deaths due to Carcinoma after LCIS The CPMC report mentioned 6 deaths due to carcinoma after LCIS but did not include a calculation of the observed to expected number of deaths due to breast cancer. In the Memorial Hospital series, deaths due to breast cancer were I I times more frequent than expected among women with untreated LCIS.

VIII. Treatment of LeIS The studies carried out at the Memorial Hospital for Cancer and Allied Diseases and at CPMC source revealed very similar trends. Yet we are not convinced that these studies provide unequivocal answers and in

452 . P. P. Rosen

this respect we continue to have a substantial difference of opinion with the CPMC group. They have recommended without reservation that patients with LCIS not be treated by mastectomy and that they be examined every four months in a life-long follow-up program. A follow-up program of the type recommended by Haagensen et al. (1978) makes little use of mammography and relies heavily on clinical examination for the detection of a palpable lesion . Since LCIS is not palpable and intraductal carcinoma rarely forms a mass, the recommended follow-up program seeks to identify infiltrating carcinomas presumably localized to the breast. However, metastases to axillary lymph nodes have been observed even in the absence of demonstrable invasive carcinoma in some patients with LCIS. This occurred in 2 patients with LCIS treated at Memorial Hospital between 1976 and 1978 (Rosen et al. , Ann. Surg., 1979). Furthermore, the potential for axillary metastases among patients with relatively small invasive carcinomas should not be underestimated. Data from the SEER Program of the National Cancer Institute (Smart et al., 1978) reported axillary metastases in 17.2% of cases with tumors less than 0.5 em in diameter and in 20.2% when the primary measured 0.5-0.9 ern. In a series of patients with non -palpable invasive carcinomas detected by mammography in a screening center, 23.1% were found to have axillary metastases (Schwartz et al., 1978). Even the most meticulous and frequent clinical examination cannot guarantee that an invasive carcinoma that developed during the follow-up of LeIS would not have metastasized before it was detected. The risk may be relativel y low, but it would be inappropriate to suggest that it is inconsequential. And, a follow-up program entails a life-long commitment on the part of patient and physician. Failure of a patient to attend all examinations regularly is a risk of the follow-up program. One cannot blame the patient if she returns after such an absence with a palpable tumor since this might equally occur between two regularly scheduled visits. We find nothing in the CPMC study that would lead us now to alter the conclusion we reached last year (Rosen et al., 1978): "T he more we learn about d isease, the less certain it appeal'S at present that an y sin gle recommendation for th erap y is appro priate fo r ali pat ient s. Until effectiv e methods of non surgical interv ention or for the d etect ion of microscopic early invasive carcinoma become ava ilabl e, the calculated risk of lifetime follo w-up may some times be an acceptable altern ativ e to the certainty of cure by mastectomy. H ow ev er, the recommend ation f or foll ow-up should onl y be made wi th full appreciation of th e risks and respons ibilities in vo lv ed and in our opinion rem ains an inv estigativ e p rocedu re. Unt il it can be dete rm.ned w hether this approach w ill result in a substantial reduction of deaths due to breast

Lobular Carcinoma in Situ . 453 carcinoma, it is considered prudent in most cases to I ecommend ipsilateral mastectomy, generally with low axillary dissection and to perform a generous contralateral biopsy. "More than a decade has already been spent in the dispute between follow-up and mastectomy. Neither of these choices is Ideal and each has Important risks and deficiencies. To advocate one to the total exclusion of the other is, in our opinion, no longer a tenable position, The decision need not be made hastily and in anyone case must be arrived at after provid:ng ample op poi tunit y to consider the known facts about the disease, the pbysician's recommendation, and the patient's desires and response to her condition. "

IX. The Future of LeIS Lobular carcinoma in situ offers a challenging opportunity for future research. Because of the scarcity of patients in most institutions and the long follow-up required most investigators are discouraged from attempting prospective studies. Yet, had a prospective investigation been set up over 10-15 years ago when the first retrospective studies were started, we would now be more than halfway toward meaningful results. Two important questions for future studies of LCIS are: a) the possibility of using predictive factors to identify patients with a high or low risk for the subsequent development of invasive carcinoma; and b) the effects of medical treatment (chemotherapy, antiestrogens or other medications) on the long-term risk for subsequent carcinoma in patients not treated surgically. We are not convinced that the best possible treatment for LCIS is simply to follow these women and to wait until a palpable invasive carcinoma appears. Nor are we entirely satisfied with our own recommendation for ipsilateral mastectomy. While today the choice of therapy for any one patient must be made from available data, the challenge before us is an opportunity for improvement that should not be lost.

References Andersen, ]. A.: Lobular carcinoma in situ: A long-term follow-up in 52 patients. Acta path. microbial. scand. 83, 519-533 (1974) Andersen, J. A.: Lobular carcinoma in situ of the breast. Cancer 39,2597-2602 (1977) Barnes, J. P.: Bilateral lobular carcinoma in situ OJ the breast. Report of 2 cases. Texas State J. Med. 55, 581-5 84 (1959) Benfield, J. R., Jacobson, M., and Warner, N. E: In situ lobular carcinoma of the breast. Arch. Surg. 91, 130-135 (1965) 30 Path. aee, Pract. Vol. 166

454 . P . P. Rosen Betsill, W. L., Rosen, P. P., Lieberman, P. H., and Robbins, G. F.: Intraductal carcinoma. Long-term follow-up after treatment by biopsy alone. ]. Arner. med. Ass. 239, 1863186 7 (197 8) Cancer in Connecticut, Incidence Rates 1935-1962. Connecticut State Department of Health, Hartford, Conn. (1966) Cancer in Connecticut, 1966-1968, Connecticut State Department of Health, Hartford, Conn. (1971) Cancer in Connecticut, 1963, 1964, 1965, 1970, 1973. Connecticut State Department of Health, Hartford, Conn. (1975) Carter, D., and Smith, R. L.: Carcinoma III situ of the breast. Cancer 40, II89-II93 (1977) Cheatle, G. L., and Cutler, M.: Tumours of the Breast. J. B. Lippincott, Philadelphia (193 2) Cornil, V.: Les Tumeurs du Sein. Librairie Germer Bailliere and Co., Paris (1908) Dean, L., and Geschickter, C. F.: Comedo carcinoma of the breast. Arch. Surg. 36, 225-2 34 (193 8) Donegan, W. L., and Perez-Mesa, C. M.: Lobular carcinoma: an indication for elective biopsy of the second breast. Ann. Surg. 176, 178-187 (1972) Ewing, ].: Neoplastic Diseases. Third Edition. W. B. Saunders, Philadelphia (1928) Farrow, ]. H.: Current concepts in the detection and treatment of the earliest of the early breast cancers (The James Ewing lecture). Cancer 25, 458-477 (1970) Foote jr., F. W., and Stewart, F. W.: Lobular carcinoma in situ: A rare form of mammary carcinoma. Amer. J. Path. 17, 49h1-95 (1941) Godwin, J. T.: Chronology of lobular carcinoma in the breast. Report of a case. Cancer 5,259- 266 (1952) Haagensen, C. D.: Diseases of the Breast, and Edition, p. 516. W. B. Saunders, Philadelphia (1971) Haagensen, C. D.: Diseases of the Breast, znd Edition, pp, 528-544, 586-59°. W. B. Saunders, Philadelphia (1971) Haagensen, C. D., Lane, N., and Lattes, R.: Neoplastic proliferation of the epithelium of the mammary lobules. Surg. Clin. N. Amer. 52, 497-524 (1972) Haagensen, C. D., Lane, N., Lattes, R., and Bodian, C,'. Lobular neoplasia (so-called lobular carcinoma in situ) of the breast. Cancer 42, 737-769 (1978) Hutter, R. V. P., and Foote jr., F. W.: Lobular carcinoma in situ. Long term follow-up. Cancer 24, 1081-1085 (1969) Kraus, F. T., and Neubecker, R. D.: The differential diagnosis of papillary tumors of the breast. Cancer 15,444-455 (19 62) Lewison, E. F., Finney jr., G. G.: Lobular carcinoma in situ of the breast. Surg. Gynec. Obstet, 126, 1280-1286 (1968) McDivitt, R. W., Hutter, R. V. P., Foote jr., F. W., and Stewart, F. W.: In situ lobular carcinoma: A prospective follow-up study indicating cumulative patient risks. ]. Amer. med. Ass. 201, 82-86 (1967) Newman, W.: In situ lobular carcinoma of the breast. Report of 26 women with 32 cancers. Ann. Surg. [57, 591-599 (19 63) Rosen, P. P.: Frozen section diagnosis of breast lesions. Recent experience with 556 consecutive biopsies. Ann. Surg. 187, 17-19 (1978) Rosen, P. P., Fracchia, A. A., Urban, J. A., Schottenfcid, D., and Robbins, G. F· "Residual" mammary carcinoma following simulated partial mastectomy. Cancer 35, 739-747 (1975)

Lobular Carcinoma in Situ . 455 Rosen, P. P., and Lieberman, P. H.: Lobular carcinoma in situ: preliminary results of a long term follow-up study. In Early Diagnosis of Breast Cancer, pp. 119-127. E. Grundman and L. Beck (Eds.) (Cancer campaign series. Vol. I). Gustav Fischer, New York (1978) Rosen, P. P., Lieberman, P. H., Braun jr., D. W., Kosloff, c., and Adair, F.: Lobular carcinoma in situ of the breast: Detailed analysis of 99 patients with average followup of 24 years. Amer. ]. Surg. Path. 2, 22. 5-2 51 (1978) Rosen, P. P., and Braun jr., D. W.: The Clinical significance of preinvasive breast carcinoma. Cancer (In press) Rosen, P. P., Senie, R. T., Farr, G. H., Schottenfeld, D .. and Ashikari, R.: Epidemiology of breast carcinoma: age, menstrual status and exogenous hormone usage in patients with lobular carcinoma in situ. Surgery 85,219-224 (1979) Rosen, P. P., Senie, R. T., and Ashikari, R.: Non-invasive breast carcinoma: Frequency of unsuspected invasion and implications for treatment. Ann. Surg. 189, 377-382 (1979) Salomon, A.: Bcitrage zur Pathologie und Klinik der Mammacarcinome. Arch. klin. Chir. IOI, 573-668 (1913) Schwartz, G. E, Feig, S. A., and Patchefsky, A. S.: Clinicopathologic correlations and significance of clinically occult mammary lesions. Cancer 4I, 1147-1153 (1978) Shah, J. P., Rosen, P. P., and Robbins, G. E: Pitfalls of local excision in the treatment of carcinoma of the breast. Surg. Gynec. Obstet. 136, 721-725 (1973) Smart, C. R., Myers, M. H., and Gloeckler, L. A.: Implications from SEER data on breast cancer management. Cancer -1I, 787-789 (1978) Urban, ]. A.: Bilaterality of cancer of the breast - biopsy of the opposite breast. Cancer 20, 1867-1870 (1967) Urban, ]. A.: Biopsy of the "normal" breast in treating breast cancer. Surg. Clin. N. Amer. 49,291-301 (1969)

Received and accepted January

22,

1979

Key words: Breast cancer - Lobular carcinoma in situ Paul Peter Rosen, M.D., Department of Pathology, Memorial Hospital, 1275 York Avenue, New York, N.Y. 100H, U.S.A.